Tributaries of the 2023 Nobel Prize in Physiology or Medicine, and lessons learned.

Almost without exception, scientific breakthroughs are not epistemological orphans. Historians of science have developed a body of scholarship on this, and the cases arising in our era continue to confirm the phenomenon. The work by Katalin Karikó and Drew Weissman that proved foundational for the subsequent development of mRNA vaccines for COVID-19 had its antecedent roots yet is also a striking example of both serendipity and their persistence. Their receipt of the 2023 Nobel Prize in Physiology or Medicine was greatly deserved and, as Alfred Nobel likely envisioned the broad impact to be for all the prizes, affirms to the public at large that there is such a thing as the scientific method, and that there are such things as facts. The importance of society recognizing this has always been critically important, perhaps never more so than now.

An Intermittent Cytochemist.

I wanted to be a cytochemist but encountered detours and then, in some of my work, became one of a different kind than classically defined. I recount this here to discourage young scientists from regarding cytochemistry as something that peaked in the past, but rather to be viewed as an entirely new form of the discipline, and so rich with opportunities. (J Histochem Cytochem 71: 475-480, 2023).

Nucleolar structure connects with global nuclear organization.

The nucleolus is a multifunctional nuclear body. To tease out the roles of nucleolar structure without resorting to the use of multi-action drugs, we knocked down the RNA polymerase I subunit RPA194 in HeLa cells by siRNA. Loss of RPA194 resulted in nucleolar-structural segregation and effects on both nucleolus-proximal and distal-nuclear components. The perinucleolar compartment was disrupted, centromere clustering around nucleoli was significantly reduced, and the intranuclear locations of specific genomic loci were altered. Moreover, Cajal bodies, distal from nucleoli, underwent morphological and some compositional changes. In comparison, when the preribosomal RNA-processing factor, UTP4, was knocked down, neither nucleolar segregation nor the intranuclear effects were observed, demonstrating that the changes of nucleolar proximal and distal nuclear domains in RPA194 knockdown cells unlikely arise from a cessation of ribosome synthesis, rather from the consequence of nucleolar-structure alteration. These findings point to a commutative system that links nucleolar structure to the maintenance and spatial organization of certain nuclear domains and genomic loci.

Nucleolar structure connects with global nuclear organization.

The nucleolus is a multi-functional nuclear body. To tease out the roles of nucleolar structure without resorting to multi-action drugs, we knocked down RNA polymerase I subunit RPA194 in HeLa cells by siRNA. Loss of RPA194 resulted in nucleolar structural segregation and effects on both nucleolus-proximal and distal nuclear components. The perinucleolar compartment was disrupted, centromere-nucleolus interactions were significantly reduced, and the intranuclear locations of specific genomic loci were altered. Moreover, Cajal bodies, distal from nucleoli, underwent morphological and compositional changes. To distinguish whether these global reorganizations are the results of nucleolar structural disruption or inhibition of ribosome synthesis, the pre-ribosomal RNA processing factor, UTP4, was also knocked down, which did not lead to nucleolar segregation, nor the intranuclear effects seen with RPA195A knockdown, demonstrating that they do not arise from a cessation of ribosome synthesis. These findings point to a commutative system that links nucleolar structure to the maintenance and spatial organization of certain nuclear bodies and genomic loci.

"Mechanism"-a misused term?

Many of us use the term "mechanism" when we shouldn't. Here I offer some thoughts, especially as guidance for young scientists.

A conundrum in 3-D genome organization and expression?

Recent advances in our understanding of how the genome is folded within the nucleus have included cases in which this positioning correlates with gene expression, either positively or negatively. But is the 3-D location of a gene a cause or an effect of its expression? In this Perspective I articulate the problem and then cite as guideposts recent cases where causation has indeed been arguably established. The hope is to critically illuminate this issue for continued consideration in this important, evolving field.

The nuclear bodies conference: Hubs of genomic activity, June 24-28, Western Shore, Nova Scotia, Canada.

This conference brought together leaders in the investigation of various bodies that populate the nucleus, a field that complements research on chromosome biology. These nuclear bodies had been receiving increasing attention as hubs of genome activity and the new findings reported at the conference strongly confirmed and significantly expanded this principle.

Dissecting cellular diversity of cortical GABAergic cells across multiple modalities: A turning point in neuronal taxonomy.

Decoding the complexity of the brain requires an understanding of the architecture, function, and development of its neuronal circuits. Neuronal classifications that group neurons based on specific features/behaviors have become essential to further analyze the different subtypes in a systematic and reproducible way. A comprehensive taxonomic framework, accounting for multiple defining and quantitative features, will provide the reference to infer generalized rules for cells ascribed to the same neuronal type, and eventually predict cellular behaviors, even in the absence of experimental measures. Technologies that enable cell-type classification in the nervous system are rapidly evolving in scalability and resolution. While these approaches depict astonishing diversity in neuronal morphology, electrophysiology, and gene expression, a robust metric of the coherence between different profiling modalities leading to a unified classification is still largely missing. Focusing on GABAergic neurons of the cerebral cortex, Gouwens et al.1 pioneered the first integrated cell-type classification based on the simultaneous analysis of the transcriptional networks, the recording of intrinsic electrophysiological properties, and the reconstruction of 3D morphologies of the same cell. Their comprehensive and high-quality data provide a new framework to shed light on what may be considered a "neuronal cell type."